3-Alkanoyl benzothiazoline compounds useful for treating cardiovascular disease

ABSTRACT

The invention relates to benzothiazoline derivatives of the formula [I] and salts thereof, which are useful for (i) treating cardiovascular diseases, and (ii) as the active ingredient of pharmaceutical compositions. Formula [I] follows: ##STR1## wherein R 1  is lower alkanoyl; 
     R 2  is one or more group(s) selected from hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen, nitro, halogenolower alkyl and sulfamoyl; 
     R 3  is ##STR2## R 4  and R 5  each is hydrogen, lower alkyl, cyclohexyl or substituted lower alkyl; 
     Z is straight or branched alkylene containing 1 to 6 carbon atoms; 
     m is 0 or 1; n is 0 or 1; and p is 4 or 5.

TECHNICAL FIELD OF THE INVENTION

This is a division of application Ser. No. 503,160 filed Apr. 14, 1983 now U.S. Pat. No. 4,479,949, issued Oct. 30, 1984.

This invention relates to benzothiazoline derivatives of the formula [I] and salts thereof, ##STR3## wherein R¹ is lower alkanoyl;

R² is one or more group(s) selected from hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen, nitro, halogeno-lower alkyl and sulfamoyl;

R³ is ##STR4## or --COR⁸ ; R⁴ and R⁵, which may be same or different, each is hydrogen, lower alkyl, cyclohexyl or substituted lower alkyl wherein the substituent(s) is/are selected from the group consisting of hydroxy, phenyl, pyridyl, piperidyl or phenylcarbonyl, and said phenyl nucleus may be resubstituted by one or more groups selected from lower alkyl, hydroxy, halogen, lower alkoxy, nitro, cyano, acetamino and lower alkylamino;

R⁶ is hydrogen, alkyl containing 1 to 8 carbon atoms, alkanoyl containing 2 to 8 carbon atoms, alkenoyl containing 2 to 8 carbon atoms or furylcarbonyl, each of which alkyl, alkanoyl and alkenoyl may be substituted by one or more groups selected from hydroxy, phenyl and phenylcarbonyloxy, and said phenyl nucleus may be resubstituted by one or more groups selected from lower alkyl, hydroxy, halogen, lower alkoxy, nitro, cyano, acetamino and lower-alkylamino;

R⁷ is hydrogen, hydroxy, phenyl-lower alkyl or benzoyl;

R⁸ is hydroxy, lower alkoxy, ##STR5## Z is straight or branched alkylene containing 1 to 6 carbon atoms; m is 0 or 1;

n is 0 or 1;

p is 4 or 5,

wherein the terms lower alkyl, lower alkoxy and lower alkanoyl refer to groups having 1 to 6 carbon atoms.

The same shall be applied hereinafter.

BACKGROUND OF THE INVENTION

The compounds of this invention are novel benzothiazoline derivatives wherein the substituent at 3-position on the benzothiazoline ring is lower alkanoyl and that at 2-position is phenyl which is resubstituted by ether group at any position. 2-Phenylbenzothiazoline derivatives were reported by H. Breuer et al. (U.S. Pat. No. 3,720,683), H. D. Cossey et al. (J. Chem. Soc., 1965, 954) and P. J. Palmer et al. (J. Med. Chem., 14, 248). The U.S. Pat. of Breuer et al. relates to 2-phenylbenzothiazoline derivatives in which phenyl nucleus is substituted by alkyl, etc. but not ether group, and the pharmacological effects are for anti-inflammatory and anti-microbiral. Cossey et al. and Palmer et al. reported 2-phenylbenzothiazoline derivatives in which phenyl nucleus is substituted by ether group, but the substituent of 3-position is not lower alkanoyl but hydrogen, alkyl, benzyl, etc., and the pharmacological effect is for anti-microbial.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to benzothiazoline derivatives of the formula [I]. ##STR6##

The compounds of this invention are benzothiazoline derivatives wherein the substituent at 3-position on the benzothiazoline ring is lower alkanoyl and that at 2-position is phenyl which is resubstituted by ether group at any position. The compounds of this invention are not only new in chemical structure but also found useful for treatment of cardiovascular diseases and such effect on cardiovascular diseases has not been found in the known benzothiazoline derivatives. Cardiovascular diseases are angina cordis, arrhythmia, thrombosis, etc., and β-blocker, inhibitor of platelet aggregation, calcium antagonist, etc. are used as therapeutic agent. From the pharmacological tests, it is proved that the compounds of this invention possess a superior platelet anti-aggregation effect and calcium antagonization, so they are useful for cardiovascular diseases. Processes for preparing the compounds of this invention are summarized as follows. The reaction of the compound of the formula [II] with the compound of the formula [III], ##STR7## wherein X is halogen (the same shall be applied hereinafter), or the reaction reversed the above reaction order, i.e., the reaction of the compound of the formula [IV] with the amine derivative, ##STR8## wherein Y is halogen, carboxy or formyl, and Y and --OH may be jointed to form epoxy ring;

Amine derivative is ##STR9## q is 0 or 1, the same shall be applied hereinafter.

The processes are explained in detail as follows. The reaction of the hydroxy derivative of the formula [II] with the halide of the formula [III] needs no specific conditions, and known methods which are generally used for a reaction or hydroxy derivative with halide can be employed, but preferably the reaction is carried out in organic solvent (for example, dimethylformamide) in the presence of base (for example, NaH). The reaction of the compound of the formula [IV] with amine derivative is divided into the following (a)-(d) reactions. ##STR10## Specific conditions are unnecessary for the above-mentioned reactions. Methods which are generally used for a reaction of amine derivative with halide, carboxylic acid derivative, aldehyde derivative or epoxy derivative can be employed.

The compounds of this invention can be converted to acid salts. Said salts are obtained by general methods using inorganic acids or organic acids. Examples of pharmaceutically acceptable salts of the compounds are hydrochloride salt, sulfuric acid salt, phosphoric acid salt, lactic acid salt, maleic acid salt, fumaric acid salt, methanesulfonic acid salt, p-toluenesulfonic acid salt, oxalic acid salt, etc.

The compounds of the formula [I] have stereoisomers because of the existence of one or more asymmetric carbon atoms, and these isomers are included in this invention.

Examples are shown below, and the compounds of this invention are listed in Table I-IX.

The assignments of the NMR spectra in Table X are made according to the numbers of the formula [IX]. ##STR11## But, protons (aromatic), not be assigned, are named as aromatic H (Ar--H). Proton of --OCH₃ group is assigned as --OCH₃ (P) when the group is attached to C₂ '-C₆ ' position of the formula [IX], and assigned as --OCH₃ (A) when the group is attached to the phenyl group which is the substituent of amine moeity of the side chain.

EXAMPLE 1 3-Acetyl-2-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]benzothiazoline hydrochloride (Compound No. 86)

1.31 g of 3-acetyl-2-[2-(2,3-epoxypropoxy)phenyl]benzothiazoline and 4.21 ml of t-butylamine are dissolved in 10 ml of ethanol and the solution is refluxed for 1 hour. After cooling, 2 ml of 2N HCl/ethyl acetate is added to the reaction mixture and the solution is concentrated in vacuo. To the residue ether is added to produce crystals. Crystals are collected by filtration to give 1.3 g (81%) of the titled compound.

Physical data are shown in Table VII.

The compounds shown in Table VII are prepared by the similar method descrived above using corresponding amine derivatives.

EXAMPLE 2 3-Acetyl-2-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]benzothiazoline hydrochloride (Compound No. 86)

1.64 g of 3-acetyl-2-[2-(2,3-epoxypropoxy)phenyl]benzothiazoline, 1.82 g of 3-acetyl-2-[2-(3-chloro-2-hydroxypropoxy)phenyl]benzothiazoline and 10 ml of t-butylamine are dissolved in 30 ml of ethanol and the solution is refluxed for 3 hours. The solution is concentrated in vacuo, and the residue is dissolved in ethyl acetate. The solution is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. To this solution 2N HCl/ether is added to produce crystals. Crystals are filtered to give 3.5 g (80%) of the titled compound.

The physical constant of the crystals is the same of the compound obtained in Example 1.

EXAMPLE 3 3-Acetyl-2-[2-(3-dimethylaminopropoxy)phenyl]benzothiazoline (Compound No. 7)

To the suspension of 0.26 g of the sodium hydride in anhydrous DMF, the solution of 1.36 g of 3-acetyl-2-(2-hydroxyphenyl)benzothiazoline in 5 ml of anhydrous DMF is added dropwise under nitrogen atmosphere at room temperature. After the addition, the reaction mixture is stirred for 20 minutes at room temperature. To the reaction mixture, the solution of 0.61 g of 3-dimethylaminopropyl chloride in 10 ml of anhydrous DMF is added. The reaction mixture is stirred for 2 hours at 80° C., and washed with n-hexane after cooling and poured into ice-water. The separated oil is extracted with ethyl acetate. The organic layer is washed with N--NaOH solution, water and saturated sodium chloride solution in the order named and dried over anhydrous magnesium sulfate. Ethy acetate is removed off in vacuo to give 1.0 g (56%) of the titled compound.

Physical data are shown in Table I.

The compounds shown in Table I, II and III are prepared by the similar method described above using corresponding benzothiazoline derivatives and substituted aminoalkyl halides.

EXAMPLE 4 3-Acetyl-2-[2-(3-aminopropoxy)phenyl]benzothiazoline hydrochloride (Compound No. 1)

By substituting 0.83 g of 3-aminopropyl bromide for 3-dimetylaminopropyl chloride in the procedure of Example 3, 1.2 g of the titled compound is obtained.

Physical data are shown in Table I.

EXAMPLE 5 3-Acetyl-2-[2-(3-diethylaminopropoxy)phenyl]benzothiazoline hydrochloride (Compound No. 10)

To the solution of 3.48 g of 3-acetyl-2-[2-(3-chloropropoxy)phenyl]benzothiazoline in 20 ml of ethanol, 10.3 ml of diethylamine is added and the mixture is refluxed for 2 hours. After removal of ethanol and excess amount of diethylamine in vacuo, ethyl acetate and water are added to the residue. The organic layer is extracted with N-hydrochloric acid, the acidic layer is alkalinized with N-sodium hydroxide solution and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed off in vacuo and the resulting oil is dissolved in methanol. To the solution hydrochloric acid in ethyl acetate is added to give 3.4 g (80%) of the titled compound.

Physical data are shown in Table I.

The compounds shown in Table I, II, III and VIII are prepared by the similar method described above using corresponding benzothiazoline derivatives and amine derivatives.

EXAMPLE 6 3-Acetyl-2-[2-(3-methylaminopropoxy)phenyl]benzothiazoline fumarate (Copmpound No. 2)

To the solution of 6.55 g of 3-acetyl-2-[2-(3-oxopropoxy)phenyl]benzothiazoline in 100 ml of methanol, 8.10 g of methylamine hydrochloride and 10.0 g of molecular sieves(3A), smashed into fine pieces, are added. To the suspension 1.26 g of sodium cyano borohydride is added and the mixture is stirred for 1 hour at room temperature. 2N-Hydrochloric acid is added to the reaction mixture and methanol is removed off in vacuo. The aqueous layer is washed with ethyl acetate and alkalinized with 2N-sodium hydroxide solution and extracted wiht ethyl acetate. The organic layer is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed off in vacuo and the resulting oil is dissolved in methanol. To the solution fumaric acid and ethyl acetate are added to give 4.9 g (65%) of the titled compound.

Physical data are shown in Table I.

EXAMPLE 7 3-Acetyl-2-[2-[5-(N-cyclohexyl-N-methlamino)pentyloxy]-5-methoxyphenyl]benzothiazoline fumarate (Compound No. 21)

By substituting 4.50 g of 3-acetyl-2-[2-(5-bromopentyloxy)-5-methoxyphenyl]benzothiazoline for 3-acetyl-2-[2-(3-chloropropoxy)phenyl]benzothiazoline and 3.40 g of N-methylcyclohexylamine for diethylamine in the procedure of Example 5, 4.2 g (70%) of the titled compound is obtained.

Physical data are shown in Table I.

The compounds shown in Table I are prepared by the similar method described above using corresponding benzothiazoline derivatives and amine derivatives.

EXAMPLE 8 3-Acetyl-2-[3-[3-(N-cyclohexyl-N-methylamino)propoxy]-4-hydroxyphenyl]benzothiazoline fumarate (Compound No. 37)

3.64 g of 3-acetyl-2-[3-(3-chloropropoxy)-4-hydroxyphenyl]benzothiazoline and 3.40 g of N-methylcyclohexylamine are stirred at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture is dissolved in 50 ml of chloroform, the solution is washed with N-hydrochloric acid, N-sodium hydroxide solution and saturated sodium chloride solution in the named order and dried over anhydrous magnesium sulfate. Chloroform is removed off in vacuo and the residue is purified by silica gel column chromatography. The oily product is dissolved in 20 ml of ethyl acetate. To the solution 0.71 g of fumaric acid in 3 ml of methanol is added to give 2.78 g (50%) of the titled compound.

Physical data are shown in Table II.

The compounds shown in Table II and III are prepared by the similar method described above using corresponding bnezothiazoline derivatives and amine derivatives.

EXAMPLE 9 3-Acetyl-2-[2-[2-[4-(3,4-dimethoxyphenetyl)-1-piperazinyl]ethoxy]phenyl]benzothiazoline dimaleate (Compound No. 57)

3.34 g of 3-acetyl-2-[2-(2-chloroethoxy)phenyl]benzothiazoline and 5.01 g of 1-(3,4-dimethoxyphenetyl)piperazine are stirred at 110° C. for 1 hour. After cooling to room temperature, the reaction mixture is dissolved in 50 ml of chloroform, the solution is washed with N-hydrochloric acid, N-sodium hydroxide solution and saturated sodium chloride solution in the named order and dried over anhydrous magnesium sulfate. Chloroform is removed off in vacuo and the resulting oil is dissolved in 50 ml of ethyl acetate. To the solution 2.32 g of maleic acid in 30 ml of ethyl acetate is added to give 6.24 g (80%) of the titled compound.

Physical data are shown in Table IV.

The compounds shown in Table I, IV, V, VI and VIII are prepared by the similar method described above using corresponding benzothiazoline derivatives and amine derivatives.

EXAMPLE 10 3-Acetyl-2-[2-[3-(ethoxycarbonyl)propoxy]phenyl]benzothiazoline (Compound No. 97)

To the suspension of 1.59 g of sodium hydride in 30 ml of anhydrous DMF, the solution of 8.13 g of 3-acetyl-2-(2-hydroxyphenyl)benzothiazoline in 30 ml of anhydrous DMF is added dropwise under nitrogen atmosphere at room temperature. After the addition, the reaction mixture is stirred for 20 minutes at room temperature. To the reaction mixture, the solution of 4.95 g of ethyl 4-chlorobutyrate in 15 ml of anhydrous DMF is added and stirred for 5 hours at 70° C. After cooling to room temperature the reaction mixture is poured into ice-water and extracted with ethyl acetate.

The organic layer is washed with N-potassium hydroxide solution, water, N-hydrochloric acid and saturated sodium chloride solution in the named order and dried over anhydrous magnesium sulfate. The solvent is removed off and the resulting oil is purified by silica gel column chromatography to give 8.67 g (75%) of the titled compound.

Physical data are shown in Table IX.

EXAMPLE 11 3-Acetyl-2-[2-[3-(carboxy)propoxy]phenyl]benzothiazoline (Compound No. 96)

To the solution of 7.71 g of 3-acetyl-2-[2-[3-(ethoxycarbonyl)propoxy]phenyl]benzothiazoline in 50 ml of methanol, 2N-sodium hydroxide solution is added and the reaction mixture is stirred for 2 hours at room temperature. Methanol is removed off in vacuo. The residue is acidified with 2N-hydrochloric acid to give 5.72 g (80%) of the titled compound.

Physical data are shown in Table IX.

EXAMPLE 12 3-Acetyl-2-[2-[3-(morpholinocarbonyl)propoxy]phenyl]benzothiazoline (Compound No. 100)

To the solution of 1.79 g of 3-acetyl-2-[2-[3-(carboxy)propoxy]phenyl]benzothiazoline and 0.51 g of triethylamine in 20 ml of anhydrous methylene chloride, 0.68 g of isobutyl chloroformate is added dropwise while stirring at -13° C. and stirred additional 10 minutes at the same temperature. To the solution 0.44 g of morpholine in 5 ml of methylene chloride is added dropwise.

After the addition, the reaction mixture is stirred for 1 hour under ice-water cooling and for 1 hour at room temperature. The reaction mixture is washed with 5% citric acid solution, water, N-potassium hydroxide solution and saturated sodium chloride solution in the named oder and dried over anhydrous magnesium sulfate. The solvent is removed off in vacuo to give 1.60 g (75%) of the titled compound.

Physical data are shown in Table IX.

The compounds shown in Table IX are prepared by the similar method described above using corresponding amine derivatives.

                                      TABLE I                                      __________________________________________________________________________      ##STR12##                                                                                                       Method                                                                         of                                                                             prepn.   mp (°C.)                     Compd.                            (Examp.                                                                             Yield                                                                              (Recrystn.                          No.  R.sup.2                                                                             R.sup.4 R.sup.5       r No.) (%) solvent)  IR(KBr,                   __________________________________________________________________________                                                          cm.sup.-1)                 1*.sup.1                                                                           H    H       H             3 4    65  106-109 (dec.)                                                                           3400, 1660, 1466,                                                              1382, 1232, 748            2*.sup.2                                                                           H    H       CH.sub.3      3 6    65  111-113   3420, 1674, 1458,                                                              1370, 724, 616             3*.sup.1                                                                           H    H       C(CH.sub.3).sub.3                                                                            4 5    75  193-195   3500, 3430, 2950,                                                              2770, 1667, 1585,                                                              1455, 1371, 1320,                                                              1266, 1221, 1095,                                                              741                        4*.sup.1                                                                           H    H                                                                                       ##STR13##    3 5    75  235.5-238.0 (dec.)                                                                       3020, 2940, 1678,                                                              1598, 1488, 1462                                                               1376, 1244, 1226,                                                              1098, 744                  5*.sup.1                                                                           H    H                                                                                       ##STR14##    3 5    70  165-169   3420, 2940, 1676,                                                              1514, 1462, 1378,                                                              1324, 1262, 1250,                                                              1228, 1022, 746            6*.sup.1                                                                           H    CH.sub.3                                                                               CH.sub.3      2 3    80  209-210   3430, 1670, 1460,                                                    (MeOHAcOEt)                                                                              1387, 1354, 1325,                                                              1272, 1245, 1230,                                                              1170, 1103, 1050,                                                              1022, 930, 750            7.sup.                                                                              H    CH.sub.3                                                                               CH.sub.3      3 3    56  92.5-94.5 1678, 1600, 1466,                                                    ((Me.sub.2 CH).sub.2 O                                                                   1376, 1312, 1274,                                                    hexane)   1246, 1218, 1006,                                                              746                        8*.sup.1                                                                           H    CH.sub.3                                                                                ##STR15##    3 5    75  130-142 (MeOHAcOEt)                                                                      3400, 2930, 2910,                                                              1672, 1464, 1380,                                                              1322, 1272, 1242,                                                              1224, 750                  9*.sup.3                                                                           H    CH.sub.3                                                                               CH.sub.2 Ph   3 5    80  159-162   3450, 1676, 1580,                                                              1490, 1466, 1380,                                                              750, 702                  10*.sup.1                                                                           H    CH.sub.2 CH.sub.3                                                                      CH.sub.2 CH.sub.3                                                                            3 5    80  154-156   3480, 3420, 2930,                                                    (MeOHAcOEt)                                                                              1676, 1462, 1378,                                                              1320, 1270, 1240,                                                              1224, 1098, 752           11*.sup.1                                                                           H    CH.sub.2 CH.sub.3                                                                      CH.sub.2 CH.sub.3                                                                            4 5    80  amorph.   3420, 1665, 1465,                                                              1380, 1324, 1270,                                                              1230, 748                 12*.sup.1                                                                           H                                                                                    ##STR16##                                                                              ##STR17##    3 5    65  amorph.   2940, 2870, 1684,                                                              1468, 1380, 750           13*.sup.1                                                                           H    CH.sub.2 CH.sub.2 OH                                                                   CH.sub.2 CH.sub.2 OH                                                                         3 9    60  145-149   3320, 1666, 1466,                                                              1380, 1314, 1236,                                                              748                       14*.sup.1                                                                           3-OCH.sub.3                                                                         CH.sub.3                                                                               CH.sub.3      3 3    70  221-222   3410, 1665, 1580,                                                    (MeOH)    1465, 1375, 1343,                                                              1270, 1232, 1060,                                                              1030, 753, 740            15*.sup.1                                                                           3-OCH.sub.3                                                                         CH.sub.3                                                                               CH.sub.3      4 5    65  199-200   3420, 2930, 1675,                                                              1575, 1460, 1375,                                                              1268, 753, 740            16*.sup.3                                                                           3-OCH.sub.3                                                                         CH.sub.3                                                                                ##STR18##    3 5    70  amorph.   3400, 2930, 1710,                                                              1665, 1575, 1460,                                                              1370, 1268, 1055,                                                              745                       17*.sup.1                                                                           3-OCH.sub.3                                                                         CH.sub.3                                                                                ##STR19##    4 5    60  197-198   3550, 3460, 2950,                                                              1675, 1660, 1482,                                                              1466, 1380, 1272,                                                              1055, 775, 750            18*.sup.3                                                                           5-OCH.sub.3                                                                         CH.sub.3                                                                               CH.sub.3      3 3    73  165.5-166 3430, 1672, 1580,                                                    (MeOH)    1492, 1465, 1373,                                                              1207, 1053, 870,                                                               749                       19*.sup.4                                                                           5-OCH.sub.3                                                                         CH.sub.3                                                                                ##STR20##    3 5    80  191.5-192 (dec.) (CH.sub.3                                                     CNMeOH)   3420, 3180, 2860,                                                              1769, 1670, 1498,                                                              1460, 1380, 1368,                                                              1300, 1280, 1209,                                                              1060, 750, 715            20*.sup.4                                                                           5-OCH.sub.3                                                                         CH.sub.3                                                                                ##STR21##    4 5    60  147-148 (CH.sub.3 CN)                                                                    3420, 1670, 1493,                                                              1463, 1372, 1275,                                                              1240, 1208, 1037,                                                              743, 720                  21*.sup.2                                                                           5-OCH.sub.3                                                                         CH.sub.3                                                                                ##STR22##    5 7    70  155.5-157.5                                                                              3420, 2930, 1670,                                                              1466, 1380, 1275,                                                              1207                      22*.sup.4                                                                           5-OCH.sub.3                                                                         CH.sub.3                                                                                ##STR23##    6 7    55  135-137   3440, 1675, 1493,                                                              1465, 1380, 1280,                                                              1210, 1040, 750,                                                               720, 700                  23*.sup.1                                                                           5-OCH.sub.3                                                                         CH.sub.3                                                                                ##STR24##    4 9    80  amorph.   3424, 1664, 1493,                                                              1463, 1377, 1321,                                                              1272, 1262, 1236,                                                              1208, 1155, 1028                                                               748                       24*.sup.1                                                                           5-OCH.sub.3                                                                          ##STR25##                                                                             CH.sub.2 CH.sub.2 OH                                                                         4 9    70  amorph.   3336, 1664, 1493,                                                              1464, 1397, 1274,                                                              1208, 1036, 748           25*.sup.1                                                                           5-OCH.sub.3                                                                          ##STR26##                                                                              ##STR27##    4 9    75  amorph.   3424, 1668, 1510,                                                              1496, 1466, 1272,                                                              1262, 1237, 1208,                                                              1025, 750                 26*.sup.1                                                                           5-Cl CH.sub.3                                                                               CH.sub. 3     3 3    70  193-195.5 3420, 1678, 1466,                                                    ((Me.sub.2 CH).sub.2 O                                                                   1376, 1226 1110,                                                     Et.sub.2 O)                                                                              1035, 764                 27*.sup.1                                                                           3-NO.sub.2                                                                          CH.sub.3                                                                                ##STR28##    3 5    70  103-106   3420, 1668, 1598,                                                              1528, 1464, 1376,                                                              1348, 1319, 1270,                                                              1225, 742                 28*.sup.2                                                                           5-NO.sub.2                                                                          CH.sub.3                                                                               CH.sub.3      3 3    65  159-160 (dec.)                                                                           3420, 1670, 1610,                                                    (MeOHCH.sub.3 CN)                                                                        1591, 1515, 1463,                                                              1379, 1340, 1268,                                                              1225, 1078, 1032,                                                              980, 745                  29*.sup.2                                                                           5-NO.sub.2                                                                          CH.sub.3                                                                                ##STR29##    3 5    55  168-169 (dec.) (MeOHCH.sub.3                                                   CN)       3460, 1693, 1670,                                                              1588, 1512, 1461,                                                              1375, 1336, 1265,                                                              1212 1074, 741            30*.sup.2                                                                           5-NO.sub.2                                                                          CH.sub.3                                                                                ##STR30##    4 5    60  176.5-178 (dec.) (MeOHCH.sub.3                                                 CN)       3420, 1695, 1591,                                                              1510, 1465, 1379,                                                              1341, 1267, 1226,                                                              1079, 755                 31*.sup.2                                                                           5-NO.sub.2                                                                          CH.sub.3                                                                                ##STR31##    5 7    70  172-174 (dec.) (MeOHCH.sub.3                                                   CN)       3430, 1710, 1675,                                                              1591, 1511, 1467,                                                              1380, 1336, 1265,                                                              1230, 1078, 982,                                                               747                       32*.sup.2                                                                           5-NO.sub.2                                                                          CH.sub.3                                                                                ##STR32##    6 7    70  178-180 (dec.) (MeOHCH.sub.3                                                   CN)       3430, 1715, 1679,                                                              1591, 1511, 1461,                                                              1377, 1335, 1268,                                                              1227, 1077, 982,                                                               749                       33*.sup.5                                                                           5-NO.sub.2                                                                          H                                                                                       ##STR33##    3 9    55  83-85 (AcOEt)                                                                            3400, 3290, 1678,                                                              1612, 1592, 1580,                                                              1522, 1466, 1348,                                                              1338, 1268, 1080,                                                              748                       34*.sup.2                                                                           3-OCH.sub.3 5-NO.sub.2                                                              CH.sub.3                                                                                ##STR34##    3 5    65  157-159 (MeOH CH.sub.3                                                                   3420, 1705, 1677,                                                              1570, 1530, 1463,                                                              1370, 1340, 1294,                                                              1273 1213, 1194,                                                               1162, 1062, 981,                                                               763,                      __________________________________________________________________________                                                          738                        *.sup.1 Hydrochloride                                                          *.sup.2 Fumarate                                                               *.sup.3 Maleate                                                                *.sup.4 Oxalate                                                                *.sup.5 Monohydrate                                                      

                                      TABLE II                                     __________________________________________________________________________      ##STR35##                                                                                            Method                                                                         of         mp(°C.)                               Compd.                 prepn. Yield                                                                              (Recrystn.                                   No.  R.sup.2                                                                             R.sup.4                                                                            R.sup.5                                                                               r (Examp. No.)                                                                          (%) solvent)                                                                               IR(KBr, cm.sup.-1)                   __________________________________________________________________________     35*.sup.1                                                                           H    CH.sub.3                                                                           CH.sub.3                                                                              3 3      70  162-164 3420, 1716, 1680, 1606, 1586,                                                  1463, 1381, 1306, 1288, 954          36   4-OH CH.sub.3                                                                           CH.sub.3                                                                              3 8      30  oil     3340, 1675, 1585, 1510, 1480                                                   1430, 1300, 1270, 1141, 750                                                    (neat)                               37*.sup.1                                                                           4-OH CH.sub.3                                                                            ##STR36##                                                                            3 8      50  130-133 (dec.)                                                                         3400, 1670, 1575, 1510, 1462,                                                  1430, 1375, 1340, 1320, 1272,                                                  1230, 1208, 985, 745                 38*.sup.2                                                                           4-OCH.sub.3                                                                         CH.sub.3                                                                            ##STR37##                                                                            4 5      85  amorph. 3400, 1660, 1512, 1460, 1380,                                                  1340, 1255, 1135, 1020, 750          39*.sup.2                                                                           4-NO.sub.2                                                                          CH.sub.3                                                                            ##STR38##                                                                            3 5      70  115-117 3420, 1662, 1606, 1513, 1464,                                                  1375, 1343, 1314, 1272, 745          40*.sup.2                                                                           6-NO.sub.2                                                                          CH.sub.3                                                                            ##STR39##                                                                            3 5      65   69-73  3430, 1665, 1610, 1580, 1510,                                                  1468, 1378, 1318, 1290, 1226,                                                  748                                  __________________________________________________________________________      *.sup.1 Fumarate                                                               *.sup.2 Hydrochloride                                                    

                                      TABLE III                                    __________________________________________________________________________      ##STR40##                                                                                              Method                                                                         of         mp(°C.)                             Compd.                   prepn. Yield                                                                              (Recrystn.                                 No.  R.sup.2                                                                             R.sup.4                                                                              R.sup.5                                                                               r (Examp. No.)                                                                          (%) solvent)                                                                             IR(KBr, cm.sup.-1)                   __________________________________________________________________________     41*.sup.1                                                                           H    CH.sub.3                                                                             CH.sub.3                                                                              2 3      80  amorph.                                                                              3410, 1664, 1510, 1464, 1378,                                                  1234, 748                            42*.sup.1                                                                           H    CH.sub.3                                                                             CH.sub.3                                                                              3 3      75  oil   3400, 1660, 1610, 1580, 1460,                                                  1380, 1230, 1174, 750                                                          (neat)                               43*.sup.1                                                                           H    CH.sub.3                                                                             CH.sub.3                                                                              4 5      80  amorph.                                                                              3420, 2940, 1666, 1510, 1464,                                                  1376, 1244, 1174, 748                44*.sup.1                                                                           H    CH.sub.3                                                                              ##STR41##                                                                            3 5      75  amorph.                                                                              3420, 2930, 1684, 1510, 1462,                                                  1376, 1326, 1268, 1244, 1230,                                                  1174, 748                            45*.sup.1                                                                           H    CH.sub.3                                                                              ##STR42##                                                                            4 5      75  amorph.                                                                              3420, 2940, 1666, 1510, 1464,                                                  1376, 1328, 1270, 1244, 1174,                                                  748                                  46*.sup.1                                                                           H    CH.sub.2 CH.sub.3                                                                    CH.sub.2 CH.sub.3                                                                     3 5      75  amorph.                                                                              3420, 2930, 1662, 1506, 1460,                                                  1374, 1324, 1266, 1238, 1172,                                                  748                                  47   3-OH CH.sub.3                                                                              ##STR43##                                                                            3 8      40  oil   3330, 1666, 1575, 1502, 1461,                                                  1376, 1340, 1270, 1216, 1121,                                                  1025, 745 (neat)                     48*.sup.1                                                                           3-OCH.sub.3                                                                         CH.sub.3                                                                             CH.sub.3                                                                              3 3      80  amorph.                                                                              3420, 1662, 1510, 1460, 1375,                                                  1335, 1256, 1230, 1132, 1025,                                                  746                                  49*.sup.1                                                                           3-OCH.sub.3                                                                         CH.sub.3                                                                             CH.sub.3                                                                              4 5      70  amorph.                                                                              3420, 1665, 1510, 1462, 1375,                                                  1255, 1230, 1132, 1025, 750          50*.sup.1                                                                           3-OCH.sub.3                                                                         CH.sub.3                                                                              ##STR44##                                                                            3 5      75  amorph.                                                                              3420, 1666, 1512, 1465, 1378,                                                  1255, 1230, 1135, 1027, 750          51*.sup.1                                                                           3-OCH.sub.3                                                                         CH.sub.3                                                                              ##STR45##                                                                            4 5      70  amorph.                                                                              3400, 1663, 1510, 1460, 1378,                                                  1255, 1132, 1025, 746                52*.sup.1                                                                           3-NO.sub.2                                                                          CH.sub.3                                                                              ##STR46##                                                                            3 5      75  amorph.                                                                              3420, 1665, 1618, 1530, 1463,                                                  1376, 1350, 1320, 1270, 1081,                                                  1027, 749                            53*.sup.1                                                                           3-OCH.sub.3                                                                         CH.sub.3                                                                             CH.sub.3                                                                              3 5      65  amorph.                                                                              3410, 2940, 1656, 1582, 1452,             5-OCH.sub.3                          1412, 1368, 1318, 1220, 1112,                                                  740                                  54*.sup.1                                                                           3-OCH.sub.3 5-OCH.sub.3                                                             CH.sub.3                                                                              ##STR47##                                                                            3 5      60  amorph.                                                                               3440, 2950, 1664, 1588, 1462,                                                 1420, 1380, 1338, 1236, 1124,                                                  752                                  55*.sup.1                                                                           3-OCH.sub.3 5-OCH.sub.3                                                             CH.sub.3                                                                              ##STR48##                                                                            4 5      75  amorph.                                                                              3420, 2932, 1664, 1589, 1458,                                                  1419, 1379, 1327, 1271, 1229,                                                  1122                                 __________________________________________________________________________      *.sup.1 Hydrochloride                                                    

                                      TABLE IV                                     __________________________________________________________________________      ##STR49##                                                                                                 Method                                             Compd.                      of prepn.                                                                             Yield                                                                              mp (°C.)                         No.  R.sup.2                                                                             R.sup.6         r (Examp. No.)                                                                          (%) (Recrystn. solvent)                                                                      IR(KBr,                       __________________________________________________________________________                                                      cm.sup.-1)                    56*.sup.1                                                                           H    CH.sub.3        3 3      65  213-215   3400, 1664, 1460, 1376,                                                        1322,                                                                          1272, 1226, 746               57*.sup.2                                                                           H                                                                                    ##STR50##      2 9      80  181-182 (dec.) (MeOHCH.sub.3                                                             3430, 1683, 1615, 1573,                                                        1513, 1460, 1375, 1352,                                                        1319, 1259, 1222, 1095,                                                        1022, 860, 755                58*.sup.2                                                                           H                                                                                    ##STR51##      3 9      70  172-173 (dec.) (MeOHCH.sub.3                                                             3430, 1687, 1619, 1570,                                                        1515, 1460, 1378, 1352,                                                        1321, 1260, 1238, 1225,                                                        1098, 1024, 864 755,                                                           743                           59*.sup.3                                                                           H                                                                                    ##STR52##      2 9      60  144-146 (dec.) (MeOHCH.sub.3                                                             3430, 1705, 1682, 1651,                                                        1586, 1511, 1459, 1374,                                                        1263, 1223, 1152, 1022,                                                        751                           60*.sup.3                                                                           H                                                                                    ##STR53##      3 9      75  149-151 (dec.) (CH.sub.3 CN)                                                             3420, 1712, 1679, 1647,                                                        1590, 1513, 1460, 1375,                                                        1262, 1227, 11155 1023,                                                        975, 750                      61*.sup.4                                                                           H                                                                                    ##STR54##      3 9      85  131-132 (dec.) (MeOHEt.sub.2                                                             3420, 1670, 1640, 1585,                                                        1512, 1459, 1374, 1260,                                                        1138, 1022, 740               62*.sup.2                                                                           5-OCH.sub.3                                                                          ##STR55##      3 9      60  181-182 (dec.) (MeOHCH.sub.3                                                             3430, 1671, 1618, 1572,                                                        1492, 1462, 1377, 1353,                                                        1322, 1260, 1236, 1207,                                                        1155, 1099, 1025, 862,                                                         745                           63*.sup.5                                                                           5-OCH.sub.3                                                                          ##STR56##      4 9      65  197.5-198.5 (MeOHCH.sub.3 CN)                                                            3420, 1708, 1668, 1575,                                                        1495, 1461, 1373, 1295,                                                        1267, 1233, 1205, 1152,                                                        1022, 973, 743                64*.sup.2                                                                           5-OCH.sub.3                                                                          ##STR57##      5 9      70  195.5-197.5 (dec.)                                                                       3440, 1664, 1580, 1500,                                                        1466, 1381, 1208, 1023,                                                        865                           65*.sup.2                                                                           5-OCH.sub.3                                                                          ##STR58##      6 9      60  188-189 (MeOHCH.sub.3 CN)                                                                3430, 1670, 1618, 1570,                                                        1465, 1380, 1354, 1260,                                                        1240, 1210, 1027, 865         66*.sup.2                                                                           5-OCH.sub.3                                                                         CH.sub.2 CH.sub.2 OH                                                                           4 9      80  186-187 (dec.)                                                                           3480, 1700, 1672, 1620,                                                        1575,                                                                (MeOHCH.sub.3 CN)                                                                        1490, 1468, 1380, 1359,                                                        1276,                                                                          1210, 1070, 865, 746          67*.sup.1                                                                           5-OCH.sub.3                                                                          ##STR59##      4 9      60  239-240 (dec.)                                                                           3420, 1674, 1588, 1500,                                                        1460, 1420, 1376, 1232,                                                        1212, 1120, 1040, 758         68*.sup.2                                                                           5-OCH.sub.3                                                                          ##STR60##      4 9      80  175-177 (EtOHCH.sub.3 CN)                                                                3430, 1664, 1571, 1492,                                                        1465, 1379, 1360, 1277,                                                        1208, 1102, 1062, 864         69*.sup.5                                                                           5-OCH.sub.3                                                                          ##STR61##      4 9      70  170-173   3440, 1491, 1465, 1379,                                                        1274, 1209, 752               70*.sup.2                                                                           5-OCH.sub.3                                                                          ##STR62##      4 9      75  181-182.5 (dec.) (MeOHCH.sub.3                                                           3450, 1710, 1672, 1580,                                                        1466, 1378, 1355, 1330,                                                        1210, 1123, 862, 746          71*.sup.3                                                                           5-OCH.sub.3                                                                          ##STR63##      3 9      65  130-131 (dec.) (AcOEt)                                                                   3420, 1701, 1660, 1641,                                                        1590, 1515, 1499, 1463,                                                        1372, 1272, 1260, 1231,                                                        1207, 1140, 1023, 980,                                                         750                           72*.sup.6                                                                           5-OCH.sub.3                                                                          ##STR64##      3 9      70  175-176 (dec.) (CH.sub.3 CN)                                                             3430, 1641, 1580, 1509,                                                        1462, 1373, 1260, 1207,                                                        1136, 1022, 975, 863,                                                          745                           73*.sup.2                                                                           5-NO.sub.2                                                                          (CH.sub.2).sub.7 CH.sub.3                                                                      3 9      75  176.5-177.5                                                                              3420, 1676, 1610, 1580,                                                        1510,                                                                (MeOHCH.sub.3 CN)                                                                        1468, 1380, 1342, 1272,                                                        1080,                                                                          865, 748                      74*.sup.2                                                                           5-NO.sub.2                                                                           ##STR65##      3 9      90  156.5-158 (dec.) (MeOHCH.sub.3                                                           3420, 1660, 1573, 1508,                                                        1461, 1378, 1338, 1262,                                                        1231, 1189, 1138, 1075,                                                        1020, 860, 741, 710           75*.sup.7                                                                           5-NO.sub.2                                                                          CO(CH.sub.2).sub.6 CH.sub.3                                                                    3 9      70  90-92.5   3450, 1650, 1590, 1466,                                                        1340                                                                 (CHCl.sub.3Et.sub.2 O)                                                                   1270, 748, 712                76*.sup.2                                                                           5-NO.sub.2                                                                           ##STR66##      3 9      75  144-145 (dec.)                                                                           3410, 1661, 1572, 1508,                                                        1462, 1378, 1337, 1267,                                                        1225, 1074, 1011, 860,                                                         741                           77*.sup.2                                                                           5-NO.sub.2                                                                           ##STR67##      3 9      70  153-155 (dec.) (EtOH)                                                                    392, 1654, 1576, 1508,                                                         1465, 1381, 1340, 1270,                                                        1192, 1077, 1013, 863,                                                         745, 701                      78*.sup.8                                                                           5-NO.sub.2                                                                           ##STR68##      3 9      75  199-202 (dec.) (DMSOH.sub.2                                                              3400, 1663, 1647, 1597,                                                        1510, 1463, 1398, 1380,                                                        1339, 1271, 1225, 1168,                                                        718                           79*.sup.4                                                                           5-NO.sub.2                                                                           ##STR69##      3 9      80  181-183 (dec.) (MeOHCH.sub.3                                                             3492, 3400, 1671, 1618,                                                        1593, 1513, 1484, 1466,                                                        1384, 1339, 1273, 1229,                                                        1080, 759, 742                80*.sup.1                                                                           3-OCH.sub.3 5-NO.sub.2                                                               ##STR70##      3 9      75  147-150 (dec.) (MeOHH.sub.2                                                              3410, 1662, 1514, 1460,                                                        1374, 1338, 1291, 1236,                                                        1139, 1098, 1060, 1021,                                                        951, 747                      __________________________________________________________________________      *.sup.1 Dihydrochloride-                                                       *.sup.2 Dimaleate-                                                             *.sup.3 Fumarate-                                                              *.sup.4 Hydrochloride-                                                         *.sup.5 Difumarate-                                                            *.sup.6 Maleate-                                                               *.sup.7 Oxalate-                                                                *.sup.8 Dioxalate-                                                      

                                      TABLE V                                      __________________________________________________________________________      ##STR71##                                                                                                Method                                              Compd.                     of prepn.                                                                             Yield                                                                              mp (°C.)                          No.  R.sup.2                                                                             R.sup.6        r (Examp. No.)                                                                          (%) (Recrystn. solvent)                                                                      IR(KBr,                        __________________________________________________________________________                                                     cm.sup.-1)                     81*  4-OCH.sub.3                                                                          ##STR72##     4 9      85  168-169 (MeOHCH.sub.3 CN)                                                                3450, 1682, 1620, 1580,                                                        1515, 1460, 1375, 1359,                                                        1336, 1260, 1240, 1139,                                                        1027, 865,                     __________________________________________________________________________                                                     745                             *Dimalate-                                                               

                                      TABLE VI                                     __________________________________________________________________________      ##STR73##                                                                                                  Method                                                                         of prepn. mp(°C.)                          Compd.                       (Examp.                                                                              Yield                                                                              (Recrystn.                              No.   R.sup.2                                                                             R.sup.6         r No.)  (%) solvent)  IR(KBr,                       __________________________________________________________________________                                                      cm.sup.-1)                    82*.sup.1                                                                            H                                                                                    ##STR74##      3 9     60  175-177 (dec.) (MeOHCH.sub.3                                                             3420, 1712, 1660, 1575,                                                        1509, 1462, 1373, 1300,                                                        1260, 1233, 1171, 1024,                                                        970,  757                     83*.sup.2                                                                            3-OCH.sub.3                                                                          ##STR75##      3 9     85  164-165 (MeOHCH.sub.3 CN)                                                                3430, 1665, 1619, 1570,                                                        1510, 1460, 1375, 1353,                                                        1325, 1256, 1235, 1132,                                                        1025,  865                    84*.sup.2                                                                            3-OCH.sub.3                                                                          ##STR76##      4 9     80  167-168 (MeOHCH.sub.3 CN)                                                                3430, 1670, 1570, 1450,                                                        1370, 1355, 1325, 1255,                                                        1240, 1130, 1025,  865,                                                        750                           85*.sup.2                                                                            3-OCH.sub.3 5-OCH.sub.3                                                              ##STR77##      4 9     70  163.5-165.5                                                                              3450, 1670, 1577, 1499,                                                        1460, 1379, 1328, 1261,                                                        1236, 1122, 1024,             __________________________________________________________________________                                                      866                            *.sup.1 Difumarate                                                             *.sup.2 Dimaleate                                                        

                                      TABLE VII                                    __________________________________________________________________________      ##STR78##                                                                                      Method                                                                         of         mp(°C.)                                     Compd.           prepn. Yield                                                                              (Recrystn.                                         No.  R.sup.4                                                                              R.sup.5                                                                              (Examp. No.)                                                                          (%) solvent)                                                                               IR(KBr, cm.sup.-1)                         __________________________________________________________________________     86*  H     C(CH.sub.3).sub.3                                                                    1      81  188-192 3350, 2980, 2790, 1672, 1660,                               2          (CHCl.sub.3Et.sub.2 O)                                                                 1470, 1384, 1224,  750                     87a* CH.sub.3                                                                              ##STR79##                                                                           1      35  208-210 3225, 2940, 1686, 1464, 1382,  744         87b* CH.sub.3                                                                              ##STR80##                                                                           1      30  143-146 3350, 2940, 1672, 1464, 1382,  748         88*  CH.sub.2 CH.sub.3                                                                    CH.sub.2 CH.sub.3                                                                    1      75  amorph. 3400, 2930, 1658, 1600, 1460,                                                  1380, 1326, 1274, 1234, 1102,                                                  1028,  750                                 __________________________________________________________________________      *Hydrochloride                                                                 Compound 87a is the diastereoisomer of compound 87b.                     

                                      TABLE VIII                                   __________________________________________________________________________      ##STR81##                                                                                                  Method                                                                         of prepn. mp(°C.)                          Compd.                       (Examp.                                                                              Yield                                                                              (Recrystn.                              No.   R.sup.2                                                                             R.sup.9         r No.)  (%) solvent)  IR(KBr,                       __________________________________________________________________________                                                      cm.sup.-1)                    89*.sup.1                                                                            H                                                                                    ##STR82##      3 5     70  124-127   3430, 2940, 1674, 1466,                                                        1380,  746                    90    H                                                                                    ##STR83##      3 3     55  121-122.5 1676, 1466, 1456, 1374,                                                        1324, 1276, 1252, 1230,                                                        1116,  752                    91*.sup.2                                                                            H                                                                                    ##STR84##      3 9     75  184-186 (dec.)                                                                           3450, 1728, 1685, 1605,                                                        1465, 1384, 1280, 1254,                                                        1239,  758                    92*.sup.2                                                                            5-OCH.sub.3                                                                          ##STR85##      4 9     70  148-150 (iso-PrOH AcOEtEt.sub.2                                                          3420, 1705, 1669, 1493,                                                        1463, 1379, 1320, 1275,                                                        1237, 1207, 1140,  745        93*.sup.3                                                                            5-OCH.sub.3                                                                          ##STR86##      4 9     80  182-184 (MeOHCH.sub.3 CN)                                                                3450, 1720, 1671, 1595,                                                        1461, 1378, 1278, 1208,                                                        702                           94*.sup.3                                                                            5-NO.sub.2                                                                           ##STR87##      3 9     75  175-178 (dec.) (MeOHCH.sub.3                                                             3408, 1664, 1610, 1592,                                                        1509, 1459, 1381, 1340,                                                        1270, 1226, 1074,  744,                                                        700                           95*.sup.3                                                                            5-NO.sub.2                                                                           ##STR88##      3 9     70  190-191 (dec.) (MeOHCH.sub.3                                                             3424, 1718, 1689, 1608,                                                        1594, 1510, 1465, 1376,                                                        1339, 1269, 1195,  744,                                                        701                           __________________________________________________________________________      *.sup.1 Hydrochloride                                                          *.sup.2 Fumarate                                                               *.sup.3 Oxalate                                                          

                                      TABLE IX                                     __________________________________________________________________________      ##STR89##                                                                                              Method                                                                         of prepn. mp(°C.)                              Compd.                   (Examp.                                                                              Yield                                                                              (Recrystn.                                  No.  R.sup.8           r No.)  (%) solvent) IR(KBr, cm.sup.-1)                 __________________________________________________________________________     96   OH                3 11    80  121-122.5                                                                               3420, 1725, 1636, 1465,                                                        1387,                                                                 (AcOEtEt.sub.2 O                                                                        1272, 1242, 1231, 1176,                                                        1100,                                                                 Me.sub.2 CHOCHMe.sub.2)                                                                 1040,  745                         97   OCH.sub.2 CH.sub.3                                                                               3 10    75  oil      1735, 1679, 1601, 1491,                                                        1468,                                                                          1380, 1325, 1273, 1247,                                                        1230,                                                                          1178, 1100, 1028,  730                                                         (neat)                             98                                                                                   ##STR90##        3 12    65  amorph.  3310, 1650, 1510, 1461, 1375,                                                  321, 1257, 1230, 1023,  745         99*                                                                                 ##STR91##        3 12    80  195.5-197 (dec.) (EtOHH.sub.2 O)                                                        3430, 1652, 1465, 1376, 1328,                                                  243, 1159, 1022,  975,  747,                                                   42                                 100                                                                                  ##STR92##        3 12    75  133-134 (AcOEt)                                                                         1670, 1639, 1599, 1460, 1373,                                                  325, 1267, 1227, 1100, 1098,                                                   1028,  750                         __________________________________________________________________________      *Fumarate                                                                

      X NMR No.  δ (ppm), J =       Hz       1 DMSO-d.sub.6      ##STR93##         OC.sub.--H.sub.2), 6.60-7.40 (8H, m, C.sub.2H and ArH), 7.70-8.20      (1H, m, C.sub.4H), 8.00-8.80 (3H, br, N.sub.--H.sub.2 and .sub.--HCl)      2 DMSO-d.sub.6       ##STR94##       ##STR95##         (1H, m, C.sub.4H), 9.13 (3H, br s, N.sub.--H and CO.sub.2.sub.--H      × 2)       3 DMSO-d.sub.6      ##STR96##       ##STR97##         9.40 (2H, br, N.sub.--H and .sub.--HCl)       4 DMSO-d.sub.6      ##STR98##       ##STR99##         (1H, m, C.sub.4H), 9.50-10.53 (2H, br, N.sub.--H and .sub.--HCl)   5      DMSO-d.sub.6       ##STR100##         OC.sub.--H.sub.3), 3.74 (3H, s, OC.sub.--H.sub.3), 4.23 (2H, t, J =      6.0, OC.sub.--H.sub.2), 6.60-7.50 (11H, m, C.sub.2H and ArH), 7.70-8.10       (1H, m, C.sub.4H), 9.50 (2H, br s, N.sub.--H and .sub.--HCl)   6      DMSO-d.sub.6       ##STR101##         6.73-7.63 (8H, m, C.sub.2H and ArH), 7.80-8.23 (1H, m, C.sub.4H),      11.53 (1H, br s, .sub.--HCl)       7 CDCl.sub.3      ##STR102##         OC.sub.--H.sub.2 CH.sub.2), 6.60-7.40 (8H, m, C.sub.2H and ArH),      7.70-8.30 (1H, m, C.sub.4H)       8 DMSO-d.sub.6      ##STR103##       ##STR104##         (1H, m, C.sub.4H), 10.80-11.50 (1H, br, .sub.--HCl)   9 DMSO-d.sub.6       ##STR105##       ##STR106##       ##STR107##         CO.sub.2.sub.--H × 2)       10 DMSO-d.sub.6      ##STR108##         6H, m, C.sub.--H.sub.2 N(C.sub.--H.sub.2 CH.sub.3).sub.2), 4.22 (2H,      t, J = 5.5, OC.sub.--H.sub.2), 6.70-7.40 (8H, m, C.sub.2H and ArH),      7.70-8.10   (1H, m, C.sub.4H), 10.90-11.50 (1H, br, .sub.--HCl)  11      DMSO-d.sub.6       ##STR109##         3.40 (6H, m, C.sub.--H.sub.2 N(C.sub.--H.sub.2 CH.sub.3).sub.2),      3.90-4.33 (2H, m, OC.sub.--H.sub.2), 6.60-7.57 (8H, m, C.sub.2H and      ArH), 7.67-8.23   (1H, m, C.sub.4H), 10.63-11,40 (1H, br, .sub.--HCl)      12 DMSO-d.sub.6       ##STR110##         3.90-4.50 (2H, m, OC.sub.--H.sub.2), 6.70-7.50 (8H, m, C.sub.2H and   H      Ar), 7.70-8.10 (1H, m, C.sub.4H), 10.10-10.60   (1H, br, .sub.--HCl)  13      DMSO-d.sub.6       ##STR111##         (4H, m, C.sub.--H.sub.2 OH × 2), 4.17 (2H, t, J =               H       5.5, OC.sub.--.sub.2), 4.50-5.20 (2H, br, O.sub.--H × 2),      6.60-7.50 (8H, m,   C.sub.2H and ArH), 7.70-8.20 (1H, m, C.sub.4H),      10.00-10.60 (1H, br, .sub.--HCl)       14 DMSO-d.sub.6      ##STR112##       ##STR113##         7.40 (6H, m, C.sub.2H and ArH), 7.73-8.16 (1H, m, C.sub.4H), 10.50-11.      73 (1H, br, .sub.--HCl)       15 CDCl.sub.3      ##STR114##       ##STR115##         6.70-7.30 (6H, m, C.sub.2H and ArH), 7.56-8.30 (1H, m, C.sub.4H),      11.87-12.80 (1H, br, .sub.--HCl)       16 DMSO-d.sub.6      ##STR116##       ##STR117##         6.52 (1H, dd, J = 6.0, 3.5, C.sub.4 'H), 6.63-7.27 (6H, m, C.sub.2H      and ArH), 7.63-8.17 (1H, m, C.sub.4H), 10.00-   14.50 (2H, br, CO.sub.2.s      ub.--H × 2)       17 CDCl.sub.3      ##STR118##       ##STR119##         C.sub.4 'H), 6.57-7.30 (6H, m, C.sub.2H and ArH), 7.57-8.23 (1H, m,      C.sub.4 H), 11.40-12.23 (1H, br, .sub.-HCl)       18 CDCl.sub.3      ##STR120##       ##STR121##         C.sub.6 'H), 6.63-7.30 (6H, m, C.sub.2H and ArH), 7.57-8.30 (1H, m,      C.sub.4H), 12.65-15.50 (2H, br, CO.sub.2.sub.--H × 2)       19 DMSO-d.sub.6       ##STR122##       ##STR123##         C.sub.6 'H), 6.62-7.37 (6H, m, C.sub.2H and ArH), 7.63-8.20 (1H, m,      C.sub.4H), 9.82 (2H, br s, CO.sub.2.sub.--H × 2)  20 DMSO-d.sub.6       ##STR124##       ##STR125##         6.62-7.40 (6H, m, C.sub.2H and ArH), 7.70-8.20 (1H, m, C.sub.4H),      9.75 (2H, br s, CO.sub.2.sub.--H × 2)       21 DMSO-d.sub.6      ##STR126##       ##STR127##       ##STR128##       22 DMSO-d.sub.6      ##STR129##       ##STR130##         6.63-7.40 (6H, m, C.sub.2H and ArH), 7.67-8.20 (1H, m, C.sub.4H),      9.17 (2H, br s, CO.sub.2.sub.-- H × 2)       23 DMSO-d.sub.6      ##STR131##       ##STR132##         3.80-4.20 (2H, m, OC.sub.--H.sub.2), 6.45 (1H, d, J = 2.0, C.sub.6      'H), 6.60-7.30 (9H, C.sub.2H and ArH), 7.70-8.10   (1H, m, C.sub.4H),      10.90-11.50 (1H, br, .sub.--HCl)       24 DMSO-d.sub.6      ##STR133##         3.23 (3H, s, OC.sub.--H.sub.3 (P)), 3.70-4.00 (2H, m, C.sub.--H.sub.2      OH), 3.90-4.30 (2H, m, OC.sub.--H.sub.2), 4.67 (1H, s, O.sub.--H),      6.41 (1H, d, J = 2.0, C.sub.6 'H), 6.70-7.30 (6H, m, C.sub.2H and ArH),      7.70-8.20 (1H, m, C.sub.4H), 9.90-10.40   (1H, br, .sub.--HCl)  25      DMSO-d.sub.6       ##STR134##         3.57 (3H, s, OC.sub.--H.sub.3 (P)), 3.65 (3H, s, OC.sub.--H.sub.3      (A)), 3.71 (3H, s, OC.sub.--H.sub.3       (A)), 3.90-4.30 (2H, m, OC.sub.--H.sub.2),   6.42 (1H, d, J = 2.0,      C.sub.6 'H), 6.60-7.20 (9H, m, C.sub.2H and ArH), 7.70-8.20 (1H, m,      C.sub.4H), 10.90-11.30   (1H, br, .sub.--HCl)       26 DMSO-d.sub.6      ##STR135##       ##STR136##         m, C.sub.4H), 11.00-11.90 (1H, br, .sub.--HCl)  27 CDCl.sub.3       ##STR137##       ##STR138##         m, C.sub.4H), 7.77 (1H, dd, J = 8.0, 2.0, C.sub.4 'H), 11.30-12.20      (1H, br, .sub.--HCl)       28 DMSO-d.sub.6      ##STR139##       ##STR140##         C.sub.7H), 7.28 (1H, d, J = 9.0, C.sub.3 'H), 7.72 (1H, d, J = 3.0,      C.sub.6 'H), 7.83-8.10 (1H, m, C.sub.4H), 8.15 (1H,   dd, J = 9.0, 3.0,      C.sub.4 'H), 11.33 (2H, s, CO.sub.2.sub.--H × 2)  29 DMSO-d.sub.6       ##STR141##       ##STR142##         C.sub.2H, C.sub.5H, C.sub.6H and C.sub.7H), 7.26 (1H, d, J = 9.0,      C.sub.3 'H), 7.73 (1H, d, J = 2.5, C.sub.6 'H), 7.80-8.10 (1H,   m,      C.sub.4H), 8.17 (1H, dd, J = 9.0, 2.5, C.sub.4 'H), 9.65 (2H, br s,      CO.sub.2.sub.--H × 2)       30 DMSO-d.sub.6      ##STR143##       ##STR144##         C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.60-8.20 (1H, m,      C.sub.4H), 7.72 (1H, d, J = 2.5, C.sub.6 'H), 8.15 (1H, dd,   J = 9.0,      2.5, C.sub.4 'H), 9.73-10.52 (2H, br, CO.sub.2.sub.--H × 2)  31      DMSO-d.sub.6       ##STR145##       ##STR146##         C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.72 (1H, d,      J = 2.5, C.sub.6 'H), 7.62-8.17 (1H, m, C.sub.4H), 8.16 (1H,   dd, J =      9.0, 2.5, C.sub.4 'H), 9.32-10.08 (2H, br, CO.sub.2.sub.--H × 2)      32 DMSO-d.sub.6       ##STR147##       ##STR148##         C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.72 (1H, d, J = 2.5,      C.sub.6 'H), 7.57-8.20 (1H, m, C.sub.4H), 8.18 (1H, dd,   J = 9.0, 2.5,      C.sub.4 'H), 9.43-10.13 (2H, br, CO.sub.2.sub.--H × 2)  33      CDCl.sub.3DMSO-d.sub.6       ##STR149##       ##STR150##         7.48-7.92 (2H, m, C.sub.4H and C.sub.3 'H), 7.78 (1H, d, J = 3.0,      C.sub.6 'H), 8.12 (1H, dd, J = 9.0, 3.0, C.sub.4       'H),      ##STR151##       34 DMSO-d.sub.6      ##STR152##       ##STR153##         6.85-7.33 (4H, m, C.sub.2H, C.sub.5H, C.sub.6H and C.sub.7H), 7.38      (1H, d, J = 2.5, C.sub.4 'H), 7.67-8.10 (1H, m, C.sub.4H),   7.78 (1H,      d, J = 2.5, C.sub. 6 'H), 11.05 (2H, br s, CO.sub.2.sub.--H × 2)      35 DMSO-d.sub.6       ##STR154##       ##STR155##         7.70-8.10 (1H, m, C.sub.4H), 11.44 (2H, s, CO.sub.2.sub.--H ×      2)       36 CDCl.sub.3      ##STR156##       ##STR157##         C.sub.4H)       37 DMSO-d.sub.6      ##STR158##       ##STR159##         7.70-8.10 (1H, m, C.sub.4H), 10.00-11.37 (3H, br, CO.sub.2.sub.--H      × 2 and O.sub.--H)       38 DMSO-d.sub.6      ##STR160##       ##STR161##         and ArH), 7.73-8.10 (1H, m, C.sub.4H), 10.47-11.07 (1H, br, .sub.--HCl      )       39 DMSO-d.sub.6      ##STR162##       ##STR163##         8.10 (1H, m, C.sub.4H), 7.78 (1H, d, J = 9.0, C.sub.5       ' H), 10.71-11.32 (1H, br, .sub.--HCl)  40 CDCl.sub.3DMSO-d.sub.6       ##STR164##       ##STR165##         8.10 (1H, m, C.sub.4H), 8.23 (1H, d, J = 9.0, C.sub.3       'H), 11.30-12.00 (1H, br, .sub.--HCl)       41 DMSO-d.sub.6      ##STR166##         J = 5.0, OC.sub.--H.sub.2), 6.90-7.40 (4H, m, C.sub.2H, C.sub.5H,      C.sub.6H and C.sub.7H), 6.95 (2H, d, J = 9.0, C.sub.3 'H and C.sub.5      'H),   7.23 (2H, d, J = 9.0, C.sub.2 'H and C.sub.6 'H), 7.80-8.10 (1H,      m, C.sub.4H), 10.90-11.70 (1H, br, .sub.--HCl)       42 DMSO-d.sub.6      ##STR167##       ##STR168##         6.80 (2H, d, J = 9.0, C.sub.3 'H and C.sub.5 'H), 7.12 (2H, d, J =      9.0, C.sub.2 'H and C.sub.6       'H), 7.60-8.00 (1H, m, C.sub.4H),   11.00-11.60 (1H, br, .sub.--HCl)      43 DMSO-d.sub.6       ##STR169##       ##STR170##         6.82 (2H, d, J = 8.5, C.sub.3 'H and C.sub.5 'H), 7.29 (2H, d, J =      8.5, C.sub.2 'H and C.sub.6       'H), 7.70-8.10 (1H, m, C.sub.4H),   10.80-11.50 (1H, br, .sub.--HCl)      44 DMSO-d.sub.6       ##STR171##       ##STR172##         6.81 (2H, d, J = 9.0, C.sub.3 'H and C.sub.5 'H), 7.15 (2H, d, J =      9.0, C.sub.2 'H and C.sub.6       'H), 7.70-8.00 (1H, m, C.sub.4H),   10.70-11.30 (1H, br, .sub.--HCl)      45 DMSO-d.sub.6       ##STR173##       ##STR174##         7.30 (4H, m, C.sub.2H, C.sub.5H, C.sub.6H and C.sub.7H), 7.21 (2H, d,      J = 8.5, C.sub.2 'H and C.sub.6 'H), 7.70-8.10 (1H, m,   C.sub.4H),      10.50-11.20 (1H, br, .sub.--HCl)       46 DMSO-d.sub.6      ##STR175##         (6H, m, C.sub.--H.sub.2 N(C.sub.--H.sub.2 CH.sub.3).sub.2), 4.03 (2H,      t, J = 6.0, OC.sub.--H.sub.2), 6.80-7.40 (4H, m, C.sub.2H, C.sub.5H,      C.sub.6H and C.sub.7H),   6.83 (2H, d, J = 8.5, C.sub.3 'H and C.sub.5      'H), 7.16 (2H, d, J = 8.5, C.sub.2 'H and C.sub.6 'H), 7.70-8.00 (1H, m,      C.sub.4H),   10.70-11.30 (1H, br, .sub.--HCl)       47 CDCl.sub.3      ##STR176##       ##STR177##         C.sub.2H and ArH), 7.57-8.10 (1H, m, C.sub.4 H), 8.83-9.30 (1H, br,      O.sub.--H)       48 DMSO-d.sub.6      ##STR178##       ##STR179##         7.70-8.10 (1H, m, C.sub.4H), 10.77-11.50 (1H, br, .sub.--HCl)  49      DMSO-d.sub.6       ##STR180##       ##STR181##         7.70-8.10 (1H, m, C.sub.4H), 10.53-11.37 (1H, br, .sub.--HCl)  50      DMSO-d.sub.6       ##STR182##       ##STR183##         ArH), 7.70-8.13 (1H, m, C.sub.4H), 10.67-11.33 (1H, br, .sub.--HCl)

      X NMR No.  δ (ppm) J =       HZ                                             51 DMSO-d.sub.6       ##STR184##       ##STR185##         C.sub.2H and ArH), 7.73-8.10 (1H, m, C.sub.4H), 10.50-11.07 (1H, br,      .sub.--HCl)       52 DMSO-d.sub.6      ##STR186##       ##STR187##         (1H, m, C.sub.4H), 7.33 (1H, dd, J = 9.0, 2.5, C.sub.6 'H), 7.78 (1H,      d, J = 2.5, C.sub.2 'H), 11.17-11.85 (1H, br, .sub.--HCl)       53 DMSO-d.sub.6       ##STR188##       ##STR189##         6.98 (1H, s, C.sub.2H), 6.93-7.33 (3H, m, C.sub.5H, C.sub.6H and      C.sub.7H), 7.80-8.00 (1H, m, C.sub.4H), 10.90-11.40   (1H, br, .sub.--HCl      )       54 DMSO-d.sub.6      ##STR190##       ##STR191##         and C.sub.6 'H), 7.01 (1H, s, C.sub.2H), 7.00-7.40 (3H, m, C.sub.5H,      C.sub.6H and C.sub.7H), 7.77-8.10 (1H, m, C.sub.4H),   10.68-11.20 (1H,      br, .sub.--HCl)       55 DMSO-d.sub.6      ##STR192##       ##STR193##         C.sub.6 'H), 7.00-7.50 (4H, m, C.sub.2H, C.sub.5H, C.sub.6H and      C.sub.7H), 7.80-8.10 (1H, m, C.sub.4H), 10.70-11.20 (1H, br,   .sub.--HCl      )       56 DMSO-d.sub.6      ##STR194##       ##STR195##         C.sub.4H), 11.20-12.50 (2H, br, .sub.--HCl × 2)       57 DMSO-d.sub.6       ##STR196##       ##STR197##         11.77-13.03 (4H, br, CO.sub.2.sub.--H × 4)  58 DMSO-d.sub.6       ##STR198##         3.73 (3H, s, OC.sub.--H.sub.3 (A)), 3.77 (3H, s, OC.sub.--H.sub.3      (A)), 4.17 (2H, br t, J = 5.0, OC.sub.--H.sub.2), 6.13 (4H, s,       ##STR199##         CO.sub.2.sub.--H × 4)       59 DMSO-d.sub.6      ##STR200##       ##STR201##       ##STR202##       60 DMSO-d.sub.6      ##STR203##       ##STR204##         and ArH), 7.67-8.20 (1H, m, C.sub.4H), 10.87 (2H, br s, CO.sub.2.sub.-      -H ×  2)       61 DMSO-d.sub.6      ##STR205##         3.78 (3H, s, OC.sub.--H.sub.3 (A)), 3.82 (3H, s, OC.sub.--H.sub.3      (A)), 4.20 (2H, t, J = 6.0, OC.sub.--H.sub.2), 6.62-7.70 (13H, m,       ##STR206##       62 DMSO-d.sub.6      ##STR207##         3.57 (3H, s, OC.sub.--H.sub.3 (P)), 3.70 (3H, s, OC.sub.--H.sub.3      (A)), 3.73 (3H, s, OC.sub.--H.sub.3 (A)), 4.10 (2H, br t, J = 5.0,       ##STR208##         7.68-8.20 (1H, m, C.sub.4H), 11.37-12.83 (4H, br, CO.sub.2.sub.--H      × 4)       63 DMSO-d.sub.6      ##STR209##         3.55 (3H, s, OC.sub.--H.sub.3 (P)), 3.67 (3H, s, OC.sub.--H.sub.3      (A)), 3.70 (3H, s, OC.sub.--H.sub.3       (A)), 3.87-4.32 (2H, m, OC.sub.--H.sub.2),       ##STR210##         (1H, m, C.sub.4H), 10.83 (4H, br s, CO.sub.2.sub.--H × 4)  64      DMSO-d.sub.6       ##STR211##         3.59 (3H, s, OC.sub.--H.sub.3 (P)), 3.70 (3H, s, OC.sub.--H.sub.3      (A)), 3.74 (3H, s, OC.sub.--H.sub.3       (A)), 3.80-4.30 (2H, m, OC.sub.--H.sub.2),       ##STR212##         (1H, m, C.sub.4H), 10.90-12.20 (4H, br, CO.sub.2.sub.--H × 4)      65 DMSO-d.sub.6       ##STR213##         3.57 (3H, s, OC.sub.--H.sub.3 (P)), 3.70 (3H, s, OC.sub.--H.sub.3      (A)), 3.73 (3H, s, OC.sub.--H.sub.3       (A)), 3.87-4.33 (2H, m, OC.sub.--H.sub.2),       ##STR214##         m, C.sub.4H), 11.17-12.67 (4H, br, CO.sub.2.sub.--H × 4)  66      DMSO-d.sub.6       ##STR215##         3.53 (3H, s, OC.sub.--H.sub.3 (P)), 3.65 (2H, t, J =       5.5, C.sub.--H.sub.2 OH), 3.87-4.23 (2H, m, OC.sub.--H.sub.2), 6.12      (4H, s,       ##STR216##         9.20-11.20 (5H, br, CO.sub.2.sub.--H × 4 and O.sub.--H)  67      DMSO-d.sub.6       ##STR217##         3.59 (3H, s, OC.sub.--H.sub.3 (P)), 3.64 (3H, s, OC.sub.--H.sub.3      (A)), 3.78 (6H, s, OC.sub.--H.sub.3 × 2(A)), 3.84-4.30 (2H, m,       ##STR218##         7.80-8.10 (1H, m, C.sub.4H), 11.00-13.50 (2H, br, .sub.--HCl ×      2)       68 DMSO-d.sub.6      ##STR219##         3.56 (3H, s, OC.sub.--H.sub.3 (P)), 3.74 (3H, s, OC.sub.--H.sub.3      (A)), 3.77 (3H, s,  OC.sub.--H.sub.3 (A)), 3.79 (3H, s, OC.sub.--H.sub.3      (A)),       ##STR220##       ##STR221##       ##STR222##       69 DMSO-d.sub.6      ##STR223##       ##STR224##       ##STR225##         br s, CO.sub.2.sub.--H ×  4)       70 DMSO-d.sub.6      ##STR226##         3.59 (3H, s, OC.sub.--H.sub.3 (P)), 3.74 (3H, s, OC.sub.--H.sub.3      (A)), 3.82 (6H, s, OC.sub.--H.sub.3 × 2(A)), 3.93-4.23 (2H, m,       ##STR227##         7.37 (6H, m, C.sub.2H and ArH), 7.67-8.13 (1H, m, C.sub.4H), 9.50-11.5      0 (4H, br, CO.sub.2.sub.--H × 4)       71 DMSO-d.sub.6      ##STR228##         (3H, s, OC.sub.--H.sub.3 (P)), 3.70 (6H, s, OC.sub.--H.sub.3 ×      2(A)), 4.03 (2H, t, J = 5.0, OC.sub.--H.sub.2), 6.45 (1H, d, J = 2.0,       ##STR229##         br s, CO.sub.2.sub.--H × 2)       72 DMSO-d.sub.6      ##STR230##       ##STR231##       ##STR232##         7.70-8.10 (1H, m, C.sub.4H), 9.83-12.00 (2H, br, CO.sub.2.sub.--H      × 2)       73 DMSO-d.sub.6      ##STR233##       ##STR234##         m, C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.75 (1H,      d, J = 2.5, C.sub.6 'H), 7.70-8.37 (1H, m, C.sub.4H), 8.23 (1H,   dd, J      = 9.0, 2.5, C.sub.4 'H), 11.30-12.50 (4H, br, CO.sub.2 .sub.--H ×      4)       74 DMSO-d.sub.6      ##STR235##       ##STR236##       ##STR237##         7.72 (1H, d, J = 2.5, C.sub.6 'H), 7.77-8.10 (1H, m, C.sub.4H), 8.17      (1H, dd, J = 9.0, 2.5, C.sub.4 'H), 11.00-12.27   (4H, br, CO.sub.2      .sub.--H × 4)       75 DMSO-d.sub.6      ##STR238##       ##STR239##         6.75-7.48 (5H, m, C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3  H      '), 7.63 (1H, d, J = 2.5, C.sub.6 'H), 7.65-8.25 (2H, m,   C.sub.4H and      C.sub.4 'H), 10.38 (2H, br s, CO.sub.2 .sub.--H × 2)       76 DMSO-d.sub.6       ##STR240##       ##STR241##         8.19 (1H, dd, J = 9.0, 2.5, C.sub.4 'H), 10.50-11.92 (4H, br,      CO.sub.2 .sub.--H × 4)       77 DMSO-d.sub.6      ##STR242##       ##STR243##         6.80-7.42 (5H, m, C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3  H      '), 7.28 (5H, s, C.sub.6 .sub.--H.sub.5), 7.62-8.32 (1H, m, C.sub.4H),      7.69 (1H, d, J = 2.5, C.sub.6 'H), 8.14 (1H, dd, J = 9.0, 2.5, C.sub.4      'H), 9.00-11.75 (5H, br, CO.sub.2 .sub.--H × 4 and O.sub.--H)  78      DMSO-d.sub.6       ##STR244##       ##STR245##         m, C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.67-8.51      (3H, m, C.sub.4H, C.sub.4 ' H and C.sub.6 'H), 7.88 (2H, d, J = 8.8,       ##STR246##       79 DMSO-d.sub.6      ##STR247##       ##STR248##       ##STR249##         C.sub.4 'H), 11.64-12.51 (1H, br, .sub.--HCl)       80 CDCl.sub.3      ##STR250##         3.81 (3H, s, OC.sub.--H.sub.3 (A) ), 3.84 (3H, s, OC.sub.--H.sub.3      (A) ), 3.90 (3H, s, OC.sub.--H.sub.3       (P) ), 4.20-4.65 (2H, m, OC.sub.--H.sub.2),       ##STR251##         and .sub.--HCl × 2), 7.50 (1H, d, J = 2.5, C.sub.4 'H), 7.67      (1H, d, J = 2.5, C.sub.6 'H)       81 DMSO-d.sub.6      ##STR252##         3.70 (6H, s, OC.sub.--H.sub.3 × 2 (P, A) ), 3.73 (3H, s,      OC.sub.--H.sub.3 (A) ), 3.73-4.07 (2H, m, OC.sub.--H.sub.2), 6.13 (4H,      s,       ##STR253##         CO.sub.2 .sub.--H × 4)       82 DMSO-d.sub.6      ##STR254##       ##STR255##         6.63-7.32 (11H, m, C.sub.2H and ArH), 7.69-8.10 (1H, m, C.sub.4H),      11.42 (4H, s. CO.sub.2 .sub.--H × 4)       83 DMSO-d.sub.6      ##STR256##         3.67 (6H, s, OC.sub.--H.sub.3 × 2 (P, A) ), 3.70 (3H, s,      OC.sub.--H.sub.3 (A) ), 3.93 (2H, t, J = 6.0, OC.sub.--H.sub.2), 6.10      (4H, s,       ##STR257##       84 DMSO-d.sub.6      ##STR258##         3.70 (6H, s, OC.sub.--H.sub.3 × 2 (P, A) ), 3.73 (3H, s,      OC.sub.--H.sub.3 (A) ), 3.97 (2H, t, J = 6.0, OC.sub.--H.sub.2), 6.12      (4H, s,       ##STR259##       85 DMSO-d.sub.6      ##STR260##         3.63 (6H, s, OC.sub.--H.sub.3 ×       2 (P) ), 3.70 (3H, s, OC.sub.--H.sub.3 (A) ), 3.70-4.10 (2H, m,      OC.sub.--H.sub.2), 3.73 (3H, s, OC.sub.--H.sub.3       (A) ),      ##STR261##         (1H, m C.sub.4H), 10.50-12.00 (4H, br, CO.sub.2 .sub.--H × 4)      86 CDCl.sub.3       ##STR262##       ##STR263##         7.50-8.50 (1H, m, C.sub.4H), 8.00-10.00 (2H, br, N.sub.--Hand      .sub.--HCl)       87a DMSO-d.sub.6      ##STR264##       ##STR265##         7.50 (8H, m, C.sub.2H and ArH), 7.80-8.20 (1H, m, C.sub.4H), 9.90-11.0      0 (1H, br, .sub.--HCl)       87b DMSO-d.sub.6      ##STR266##       ##STR267##         ArH), 7.70-8.27 (1H, m, C.sub.4H), 9.70-10.80 (1H, br, .sub.--HCl)      88 CDCl.sub.3 1.43 (6H, t, J = 7.0, N(CH.sub.2 C.sub.--H.sub.3).sub.2),      2.32 (3H, s, COC.sub.--H.sub.3), 3.10-3.70 (6H, m, C.sub.--H.sub.2      N(C.sub.--H.sub.2 CH.sub.3).sub.2), 3.9-4.7   2H, m, OC.sub.--H.sub.2      CH), 4.50-5.00 (1H, br, C.sub.--H(OH)), 5.50-6.10 (1H, br, O.sub.--H),      6.60-7.40 (8H, m, C.sub.2H   and ArH), 7.50-8.30 (1H, m, C.sub.4H),      10.50-11.40 (1H, br, .sub.--HCl)       89 DMSO-d.sub.6      ##STR268##       ##STR269##         (1H, m, C.sub.4H), 10.90-11.50 (1H, br, .sub.--HCl)  90 DMSO-d.sub.6       ##STR270##       ##STR271##         C.sub.4H)       91 DMSO-d.sub.6      ##STR272##       ##STR273##         (1H, m, C.sub.4H), 10.37 (2H, br s, CO.sub.2 .sub.--H × 2)  92      DMSO-d.sub.6       ##STR274##       ##STR275##         6.80-7.50 (11H, m, C.sub.2H and ArH), 7.80-8.20 (1H, m, C.sub.4H),      9.20-9.83 (2H, br, CO.sub.2 .sub.--H × 2)       93 CDCl.sub.3      ##STR276##         3.58 (3H, s, OC.sub.--H.sub.3       (P) ), 3.85-4.50 (2H, m, OC.sub.--H.sub.2 ), 6.43 (1H, d, J = 2.0,      C.sub.6 'H), 6.67-8.12 (12H, m,   C.sub.2H and ArH), 8.13 (2H, br s,      CO.sub.2 .sub.--H × 2)       94 DMSO-d.sub.6      ##STR277##         4.06 (1H, m, C.sub.--HOH), 4.10-4.69 (2H, m, OC.sub.--H.sub.2),      6.86-7.60 (5H, m, C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7 H and C.sub.3      'H),   7.71 (1H, d, J = 2.5, C.sub.6 'H), 7.83-8.49 (1H, m, C.sub.4H),      8.13 (1H, dd, J = 9.0, 2.5, C.sub.4 'H), 8.18 (3H, s,   CO.sub.2      .sub.--H × 2 and O.sub.--H)       95 DMSO-d.sub.6      ##STR278##         4.61 (2H, m, OC.sub.--H.sub.2), 6.89-7.55 (10H, m, C.sub.2H and ArH),      7.70 (1H, d, J = 2.5, C.sub.6 'H), 7.81-8.31 (1H,   m, C.sub.4H), 8.28      (1H, dd, J = 9.0, 2.5, C.sub.4 'H), 9.48 (2H, br s, CO.sub.2 .sub.--H      × 2)  96 CDCl.sub.3 1.88-2.85 (4H, m, OCH.sub.2 C.sub.--H.sub.2      C.sub.--H.sub.2 CO.sub.2 H), 2.20 (3H, s, COC.sub.--H.sub.3), 4.10 (2H,      t, J = 5.5, OC.sub.--H.sub.2), 6.60-7.50   (8H, m, C.sub.2H and ArH),      7.70-8.50 (1H, m, C.sub.4H), 10.88 (1H, br s, CO.sub.2 .sub.--H)  97      CDCl.sub.3 1.27 (3H, t, J = 7.0, CO.sub.2 CH.sub.2 C.sub.--H.sub.3),      1.88-2.80 (4H, m, OCH.sub.2 C.sub.--H.sub.2 C.sub.--H.sub.2 CO.sub.2),      2.20 (3H, s, COC.sub.--H.sub.3), 4.12   (2H, t, J =                      )       6.0, OC.sub.--H.sub.2, 4.18 (2H, q, J = 7.0, CO.sub.2 C.sub.--H.sub.2      CH.sub.3), 6.60-7.40 (8H, m, C.sub.2H and ArH), 7.80-8.50   (1H, m,      C.sub.4H)       98 CDCl.sub.3      ##STR279##         (2H, q, J = 7.0, NHC.sub.--H.sub.2       CH.sub.2), 3.77 (3H, s, OC.sub.--H.sub.3       (A) ), 3.82 (3H, s, OC.sub.--H.sub.3 (A) ), 4.08 (2H, t, J = 5.5,      OC.sub.--H.sub.2), 5.70-6.20 (1H, br, N.sub.--H), 6.50-7.50 (11H, m,      C.sub.2H and ArH), 7.60-8.50 (1H, m, C.sub.4H)       99 DMSO-d.sub.6      ##STR280##       ##STR281##         ArH), 7.80-8.20 (1H, m, C.sub.4H), 10.70 (2H, br s, CO.sub.2 .sub.--H      ×  2)  100        CDCl.sub.3      ##STR282##         t, J = 5.5, OC.sub.--H.sub.2), 6.60-7.40 (8H, m, C.sub.2H and ArH),      7.70-8.50 (1H, m, C.sub.4H)

Pharmacological Activities

Calcium antagonists have not only potentially beneficial effects in the treatment of many diseases but also serve as valuable research tools to elucidate excitation-contraction coupling in various muscle types (A. Fleckenstein, Ann. Rev. Pharmacol., 17, 149-166, 1977). Therefore, we examined the calcium-antagonistic activity of the compounds of this invention.

Pharmacological test I

The action potentials on the smooth muscles of uterus, teania coli and portal vein are dependent on calcium ion, and therefor these smooth muscle preparations are useful for screening of calcium antagonists. We measured the calcium-antagonistic activity of the compounds by the method using guinea-pig teania coli preparation.

Isolated guinea-pig teania coil was suspended in a 20 ml organ bath with Krebs solution at 32° C. and bubbled with 5% carbon dioxide in oxygen. After equilibration, the muscle was washed with Ca⁺⁺ -free Krebs solution, and when the muscle had relaxed to basal level, it was suspended in Ca⁺⁺ -free-high-K Krebs solution.

The muscle was exposed to test compounds for 5 minutes before addition of CaCl₂, and the contraction evoked by CaCl₂ (3×10⁻⁴ M) was recorded isotonically. The calcium-antagonistic activity was represented by the concentration of test compound which elicited 50% inhibition of Ca⁺⁺ -evoked contraction (IC₅₀).

As shown in Table XI, the compounds of this invention had calcium-antagonistic activity.

Blood platelet plays an important role only in hemostasis but also in thrombosis. Platelet hyperaggregability leads to an inclease in the number of circulating platelet aggregates, which may contribute toward the development of cardiac arrythmias, cardiac arrest or myocardial infarction. These cardiovascular diseases can be prevented by inhibition of platelet aggregation. Therefor, we screened the influence of test compounds on platelet aggragation in vitro, and found that they have anti-aggregatory activity.

Pharmacological test II

Blood was obtained from an anesthetized rabbit using 0.1 volumes of 3.8% sodium citrate as anticoagulant. Platelet rich plasma(PRP) was isolated by centrifugation at 650 rpm for 10 minutes at room temperature. After preincubation of PRP (0.25 ml) with various concentrations of test compounds (14 μl) for 1 minute at 37° C., collagen (3 μg/ml:final concentration) or ADP (3 μM:final concentration) was added to induce aggregation and the aggregation profiles were monitored with RIKADENKI six-channel aggregometer. The control experiment contained saline instead of test compound.

The anti-aggregatory activity was represented by the concentration of test compound which elicited 50% inhibition of control response.

As shown in the Table XII, the compounds of this invention had anti-aggregatory activity.

                  TABLE XI                                                         ______________________________________                                         Calcium-antagonistic activity                                                  Compound No.    IC.sub.50 [M]                                                  ______________________________________                                         23              6.6 × 10.sup.-7                                          33              5.2 × 10.sup.-7                                          63              6.4 × 10.sup.-7                                          67              4.7 × 10.sup.-7                                          ______________________________________                                    

                  TABLE XII                                                        ______________________________________                                         Anti-aggregatory activity                                                      Compound No.    IC.sub.50 [M]                                                  ______________________________________                                          8              4.6 × 10.sup.-6                                          21              1.3 × 10.sup.-6                                          22              1.1 × 10.sup.-6                                          29              3.2 × 10.sup.-6                                          54              3.1 × 10.sup.-6                                          55              2.0 × 10.sup.-6                                          95              2.7 × 10.sup.-6                                          ______________________________________                                    

Toxicity test

Acute toxicity of the compounds of this invention is shown in Table XIII.

(animal)

Male ddy-SLC strain rats (4 weeks of age, weighing 19-21 g) were placed in a breeding room of constant temperature and huminity (23±1° C., 55±5%) and fed freely pellet diet and water ad. libitum for a week. Rats showing normal growth were selected for the test.

(method of administration)

Test compounds are suspended in 0.5% tragacanth suspention and administered orally in a dose of 0.5 ml/20 g body weight.

                  TABLE XIII                                                       ______________________________________                                         Compound No.   LD.sub.50 (mg/kg)                                               ______________________________________                                         29             >2,000                                                          63             ≧3,000                                                   67             >1,000                                                          ______________________________________                                    

The compounds can be administered either orally or parenterally. The dosage forms are tablet, capsule, granule, powder, suppository, injection, etc. The dose is adjusted depending on symptom, dosage form, etc., but usual daily dosage is 1 to 5,000 mg, preferably 10 to 1,000 mg, in one or a few divided doses.

Examples of formulation are shown below.

    ______________________________________                                         Example of formulation                                                         ______________________________________                                         (a) tablet                                                                     compound 8               30     mg                                             lactose                  150    mg                                             crystalline cellulose    50     mg                                             calcium carboxymethylcellulose                                                                          7      mg                                             magnesium stearate       3      mg                                             total                    240    mg                                             ______________________________________                                         compound 21              50     mg                                             lactose                  120    mg                                             crystalline cellulose    60     mg                                             calcium carboxymethylcellulose                                                                          7      mg                                             magnesium stearate       3      mg                                             total                    240    mg                                             ______________________________________                                         compound 22              60     mg                                             lactose                  120    mg                                             crystalline cellulose    60     mg                                             calcium carboxymethylcellulose                                                                          7      mg                                             magnesium stearate       3      mg                                             total                    250    mg                                             ______________________________________                                         compound 23              40     mg                                             lactose                  150    mg                                             crystalline cellulose    50     mg                                             calcium carboxymethylcellulose                                                                          7      mg                                             magnesium stearate       3      mg                                             total                    250    mg                                             ______________________________________                                         compound 33              70     mg                                             lactose                  110    mg                                             crystalline cellulose    60     mg                                             calcium carboxymethylcellulose                                                                          7      mg                                             magnesium stearate       3      mg                                             total                    250    mg                                             ______________________________________                                    

The tablets may be treated with the common film-coating and further with sugar-coating.

    ______________________________________                                         (b) granule                                                                    compound 63            30     mg                                               polyvinylpyrrolidone   25     mg                                               lactose                385    mg                                               hydroxypropylcellulose 50     mg                                               talc                   10     mg                                               total                  500    mg                                               ______________________________________                                         compound 29            50     mg                                               polyvinylpyrrolidone   25     mg                                               lactose                365    mg                                               hydroxypropylcellulose 50     mg                                               talc                   10     mg                                               total                  500    mg                                               ______________________________________                                         (c) powder                                                                     compound 54            30     mg                                               lactose                500    mg                                               starch                 440    mg                                               colloidal silica       30     mg                                               total                  1000   mg                                               ______________________________________                                         compound 67            50     mg                                               lactose                480    mg                                               starch                 440    mg                                               colloidal silica       30     mg                                               total                  1000   mg                                               ______________________________________                                         (d) capsule                                                                    compound 55            30     mg                                               lactose                102    mg                                               crystalline cellulose  56     mg                                               colloidal silica       2      mg                                               total                  190    mg                                               ______________________________________                                         compound 95            50     mg                                               glycerol               329.8  mg                                               butyl p-hydroxybenzoate                                                                               0.02   mg                                               total                  380    mg                                               ______________________________________                                    

UTILITY IN AN INDUSTRIAL FIELD

This invention offers novel compounds which are useful for therapeutic agent. 

What we claim is:
 1. A compound of the formula (I) and salts thereof, ##STR283## wherein R¹ is lower alkanoyl;R² is at least one group selected from the group consisting of hydrogen, lower-alkyl, lower-alkoxy, hydroxy, halogen, nitro, halogeno-lower-alkyl and sulfamoyl; R³ is ##STR284## R⁴ and R⁵, may be same or different and are selected from the group consisting of hydrogen, lower alkyl, cyclohexyl, phenyl-lower alkyl and substituted phenyl-lower alkyl wherein the phenyl nucleus is substituted by at least one group selected from the group consisting of lower alkyl, hydroxy, chloro, bromo, loweralkoxy, nitro, cyano, acetamino and lower alkylamino, hydroxy-lower alkyl, 3-pyridyl-lower alkyl, 1-piperidyl-lower alkyl and phenylcarbonyl-lower alkyl; Z is straight or branched alkylene having 1 to 6 carbon atoms; m is 0 or 1; n is 0 or 1;wherein the terms lower alkyl, lower alkoxy and lower alkanoyl refer to groups having 1 to 6 carbon atoms.
 2. A compound as in claim 1 wherein m is
 0. 3. A compound as in claim 1 wherein m is 1, n is 1 and Z is --CH₂ --.
 4. A compound as in claim 1 wherein R¹ is acetyl.
 5. A compound as in claim 1 wherein R² is hydrogen.
 6. A compound as in claim 2 wherein R² is methoxy or nitro.
 7. A compound as in claim 2 wherein R⁴ is methyl and R⁵ is cyclohexyl.
 8. A compound as in claim 2 wherein R⁴ is methyl and R⁵ is 2-(3,4-dimethoxyphenyl)ethyl.
 9. A compound as in claim 2 wherein R⁴ is hydrogen and R⁵ is 3-pyridylmethyl.
 10. 3-Acetyl-2-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]benzothiazoline as in claim
 1. 11. 3-Acetyl-2-[2-[3-(N-cyclohexyl-N-methylamino)propoxy]phenyl]benzothiazoline as in claim
 1. 12. 3-Acetyl-2-[2-[5-(N-cyclohexyl-N-methylamino)pentoxy]-5-methoxyphenyl]benzothiazoline as in claim
 1. 13. 3-Acetyl-2-[2-[6-(N-cyclohexyl-N-methylamino)hexyloxy]-5-methoxyphenyl]benzothiazoline as in claim
 1. 14. 3-Acetyl-2-[4-[3-(N-cyclohexyl-N-methylamino)propoxy]-3,5-dimethoxyphenyl]benzothiazoline as in claim
 1. 15. 3-Acetyl-2-[4-[3-(N-cyclohexyl-N-methylamino)butoxy]-3,5-dimethoxyphenyl]benzothiazoline as in claim
 1. 16. 3-Acetyl-2-[2-[3-(N-cyclohexyl-N-methylamino)propoxy]-5-nitrophenyl]benzothiazoline as in claim
 1. 17. 3-Acetyl-2-[2-[4-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamino]butoxy]-3-methoxyphenyl]benzothiazoline as in claim
 1. 18. 3-Acetyl-2-[5-nitro-2-[3-[(3-pyridylmethyl)amino]propoxy]phenyl]benzothiazoline as in claim
 1. 19. A pharmaceutical composition comprising (i) a compound as in claim 1 in an amount sufficient for treatment for cardiovascular diseases and at least one pharmaceutically acceptable excipient.
 20. A method of treatment for cardiovascular diseases which comprises administering a composition comprising a compound as in claim 1 and at least one pharmaceutically acceptable excipient.
 21. A compound of the formula (I) and salts thereof, ##STR285## wherein R¹ is lower alkanoyl;R² is at least one group selected from the group consisting of hydrogen, lower-alkoxy, chloro, nitro and hydroxy; R³ is ##STR286## R⁴ and R⁵ which may be same or different and are selected from the group consisting of hydrogen, lower alkyl, cyclohexyl, hydroxy-lower alkyl, phenyl-lower alkyl and substituted phenyl-lower alkyl wherein the phenyl nucleus is substituted by at least one lower alkoxy group, diphenyl-lower alkyl or 3-pyridyl-lower alkyl; Z is straight or branched alkylene having 1 to 6 carbon atoms; m is 0; n is 0 or 1,wherein the terms lower alkyl, lower alkoxy and lower alkanoyl refer to groups having 1 to 6 carbon atoms.
 22. A method of treatment for cardiovascular diseases which comprises administering a composition comprising a compound as in claim 21 and at least one pharmaceutically acceptable excipient.
 23. A compound of the formula (I) and salts thereof, ##STR287## wherein R¹ is acetyl;R² is one or more hydrogen, or one or two group(s) selected from methoxy, chloro, nitro and hydroxy; R³ is ##STR288## R⁴ and R⁵ may be same or different and are selected from the group consisting of hydrogen, lower alkyl, cyclohexyl, hydroxyethyl, benzyl and phenyl-lower alkyl wherein the phenyl nucleus is substituted by one to three methoxy group(s), 1,2-diphenylethyl or 3-pyridylmethyl; Z is straight or branched alkylene having 1 to 6 carbon atoms; m is 0; n is 0,wherein the term lower alkyl refers to a group having 1 to 6 carbon atoms.
 24. A method of treatment for cardiovascular diseases which comprises administering a composition comprising a compound as in claim 23 and at least one pharmaceutically acceptable excipient. 